This invention relates to the treatment of ophthalmic disorders. In particular, this invention relates to the topical use of certain amide derivatives of flurbiprofen or ketorolac to treat or prevent ophthalmic inflammatory and angiogenesis-related disorders of the posterior segment of the eye.
U.S. Pat. No. 3,755,427 discloses that the compound known as xe2x80x9cflurbiprofenxe2x80x9d and certain related compounds possess anti-inflammatory, analgesic and antipyretic properties and are useful for the treatment of anti-inflammatory conditions, conditions of pain, and pyretic conditions. The ""427 patent discloses therapeutic compositions comprising a compound of the invention in association with pharmaceutical excipients known for the production of compositions for oral, topical, rectal or parenteral administration. The compositions are preferably administered orally (see Col. 4, lines 58-62). According to the ""427 patent at Col. 4, lines 63-69, xe2x80x9csalts, esters, amides and alcohols derived from a compound of the invention may be used in place of a compound of the invention as such derivatives appear to be metabolised by the animal bodyxe2x80x9d and converted into the corresponding acid.
The topical use of flurbiprofen and ketorolac to treat ophthalmic inflammatory conditions is known. Flurbiprofen sodium is sold as topically administrable eye drops, including a product sold under the trade name OCUFEN(copyright) (Allergan, Inc., Irvine, Calif.). In addition, U.S. Pat. No. 4,996,209 discloses the use of S(+)-flurbiprofen, substantially free of its enantiomer, R(xe2x88x92)-flurbiprofen, as a topical ophthalmic antiinflammatory agent. Currently, however, no topically administrable amide derivative of flurbiprofen is sold for the treatment of ophthalmic disorders. Ketorolac tromethamine is sold as topically administrable eye drops under the trade name ACULAR(copyright) (Allergan, Inc., Irvine, Calif.).
U.S. Pat. No. 4,454,151 discloses the use of ketorolac and certain related acids, salts and esters for relieving, inhibiting or preventing ophthalmic diseases in mammals. Definitions of salts and esters are provided in the ""151 patent at column 3, lines 25-42. The ophthlamic diseases may be, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy, conjunctivitis, or any trauma caused by eye surgery or eye injury and which are either caused by, associated with, or accompanied by inflammatory processes. Among other ways, the compounds of the ""151 patent may be administered topically to the eye in the form of eye drops.
U.S. Pat. No. 4,230,724 discloses a method of treating vascularization of the eye as a result of traumatic injury, surgery (such as a corneal transplant procedure) or onset of diabetic retinopathy, by topically treating the eye with flurbiprofen or a pharmaceutically acceptable salt thereof.
Amide derivatives of certain ophthalmically administrable non-steroidal anti-inflammatory drugs (xe2x80x9cNSAIDSxe2x80x9d) are known. For example, U.S. Pat. No. 5,475,034 discloses topically administrable compositions containing certain amide and ester derivatives of 3-benzyolphenylacetic acid, including nepafenac, useful for treating ophthalmic inflammatory disorders and ocular pain. According to the ""035 patent at Col. 15, lines 35-39, xe2x80x9c[s]uch disorders include, but are not limited to uveitis scleritis, episcleritis, keratitis, surgically-induced inflammation and endophthalmitis.xe2x80x9d
It has now been found that certain amide derivatives of flurbiprofen and ketorolac are unexpectedly effective in treating or preventing ophthalmic inflammatory and angiogenesis-related disorders of the posterior segment of the eye when topically administered to the eye.
Among other factors, the present invention is based on the finding that amide derivatives of some ophthalmically acceptable NSAIDS are not hydrolytically bioactivated while others are. Without being bound to any theory, it is believed that ocular tissue hydrolases, particularly the hydrolases of the iris/ciliary body are selective in their ability to bioactivate or hydrolyze amide derivatives of arylacetic acid NSAIDS.
The amide derivatives of flurbiprofen and ketorolac useful in the methods of the invention are those of formulas (I) and (II) below. 
wherein
R1xe2x95x90H, C1-6(un)branched alkyl, (un)substituted (substitution as defined by Z below), xe2x80x94(CH2)nxe2x80x94Xxe2x80x94(CH2)nxe2x80x2A;
R2xe2x95x90H, C1-3 alkyl, OR3;
R3xe2x95x90H, C1-3 alkyl;
R4xe2x95x90H, Mexe2x80x94, MeOxe2x80x94, MeSxe2x80x94;
R5xe2x95x90H, Mexe2x80x94;
X=nothing (carbonxe2x80x94carbon bond), O, Cxe2x95x90O, OC(xe2x95x90O), C(xe2x95x90O)O, C(xe2x95x90O)NR3, NR3C(xe2x95x90O), S(O)n2, CHOR3, NR3;
X2, X2xe2x80x2 independently=H, F;
n=2-6;
nxe2x80x2=1-6;
n2=0-2;
A=H, OH, optionally (un)substituted aryl (substitution as defined by Z below), (un)substituted heterocycle (substitution as defined by Z below); and
Zxe2x95x90H, Cl, F, Br, I, OR3, CN, OH, CF3, R4, NO2.
The compounds of formulas (I) and (II) can readily be made by one skilled in the art. For example, amide derivatives of formulas (I) and (II) can be prepared by reacting flurbiprofen or ketorolac with the appropriate amine derivative in the presence of a coupling agent such as dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide HCl, and 4-dimethylaminopyridine or 1-hydroxybenzotriazole, in an organic solvent such as acetonitrile, tetrahydrofuran or dimethylformamide at temperatures from 0xc2x0 C. to 50xc2x0 C. The use of certain protecting groups and deprotecting steps may be necessary, as appreciated by those skilled in the art.
Preferred compounds of formulas (I) and (II) for use in the methods of the present invention are those wherein:
R1xe2x95x90H, C1-4(un)branched alkyl, (un)substituted (substitution as defined by Z below);
R2, X2xe2x80x2, R4, R5xe2x95x90H;
X2xe2x95x90F; and
Zxe2x95x90Cl, F, Br, OH.
More preferred are compounds of formulas (I) and (II) wherein R1xe2x95x90H, C1-3 alkyl. The most preferred compound of formula (I) for use in the methods of the present invention is 2-(3-fluoro-4-phenyl)-propionamide. The most preferred compound of formula (II) for use in the methods of the present invention is 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide.
According to the present invention, a therapeutically effective amount of a compound of formula (I) or (II) is administered topically to the eye to treat or prevent ophthalmic inflammatory and angiogenesis-related disorders of the posterior segment of the eye. Such disorders include, but are not limited to, surgically-induced inflammation of the posterior segment of the eye; trauma-induced inflammation of the posterior segment of the eye; cystoid macular edema; exudative macular degeneration; proliferative diabetic retinopathy; ischemic retinopathies (e.g., retinal vein or artery occlusion); retinopathy of prematurity; iritis rubeosis; cyclitis; and sickle cell retinopathy.
The compounds of formula (I) and (II) can be formulated into a variety of topically administrable ophthalmic compositions, such as solutions, suspensions, gels or ointments. The most preferred form of delivery is by aqueous eye drops, but gels or ointments can also be used. Aqueous eye drops, gels and ointments can be formulated according to conventional technology and would include one or more excipients. For example, topically administrable compositions may contain tonicity-adjusting agents, such as mannitol or sodium chloride; preservatives such as chlorobutanol, benzalkonium chloride, polyquaternium-1, or chlorhexidine; buffering agents, such as phosphates, borates, carbonates and citrates; and thickening agents, such as high molecular weight carboxy vinyl polymers, including those known as carbomers, hydroxyethylcellulose, or polyvinyl alcohol.
The amount of the compound of formula (I) or (II) used in the treatment or prevention of ophthalmic disorders according to the present invention will depend on the type of disorder to be prevented or treated, the age and body weight of the patient, and the form of preparation. Compositions intended for topical ophthalmic administration as eye drops will typically contain a compound of formula (I) in an amount of from about 0.001 to about 4.0% (w/w), preferably from about 0.01 to about 0.5% (w/w), with 1-2 drops instilled once to several times a day.
Additional therapeutic agents may be added to supplement or complement the compounds of formula (I) and (II).
The following examples are presented to illustrate various aspects of the present invention, but are not intended to limit the scope of the invention in any respect. The percentages are expressed on a weight/volume basis.